Targeting of the sheddase ADAM9 improves cardiac function after myocardial infarction

Johanna Marks (Dresden)1, K. Lorenz (Würzburg)2, F. Mejia (Lansing)3, C. Prince (Lansing)3, K. Guan (Dresden)1, A. El-Armouche (Dresden)1, E. Klapproth (Dresden)1

1Medizinische Fakultät Carl Gustav Carus der TU Dresden Institut für Pharmakologie und Toxikologie Dresden, Deutschland; 2Universitätsklinikum Würzburg Institut für Pharmakologie und Toxikologie Würzburg, Deutschland; 3Verra Therapeutics Lansing, USA


Background and Aim. Despite significant advances in the management of heart failure (HF), the prognosis remains poor and many patients suffer lifelong symptoms. Recent research highlights the importance of the “A disintegrin and metalloprotease” (ADAM) family in cardiac development, angiogenesis and heart disease. Inhibition of ADAM10, for instance, early after myocardial infarction (MI) improves survival and cardiac function by preventing an exaggerated immune response. Similar to ADAM10, ADAM9 is also involved in the development of the heart. However, its role in heart disease and post-myocardial infarction has not yet been studied.

Methods and Results. Our study utilizes human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, human cardiac tissue biopsies and pharmacological ADAM9 inhibition in mice. ADAM9 mRNA and protein expression is upregulated in HF patients and after experimental myocardial infarction in mice. Analysis of human single-cell sequencing data and mouse histologic heart tissue samples revealed ADAM9 to be most abundantly expressed in cardiomyocytes. Pharmacologic ADAM9 inhibition in mice with the inhibitory peptide VTH245 resulted in a significant but transient improvement in cardiac function after myocardial infarction. To elucidate the underlying mechanisms, bulk RNA sequencing of post-MI heart tissue samples was performed indicating that functional improvement was likely associated with altered intracellular processing of the vasoconstrictor peptide hormone ACE. On the contrary, ADAM9/IL-1β-driven inflammation and intercellular calcium processing were not affected.

Conclusion and Clinical Impact. Our data suggest that inhibition of ADAM9 augments cardiac function after myocardial infarction by modulation ACE signaling. Due to its overexpression in HF patients, ADAM9 might be a potential molecular target to improve therapy after MI. Future experiments will evaluate the therapeutic and translational value of ADAM9 inhibition with particular emphasis on the renin-angiotensin-aldosterone system.

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